The renewed threat of smallpox as a bioweapon and the emerging zoonotic threat of monkeypox highlight the need for effective poxvirus countermeasures. Use of the smallpox vaccine poses a serious health risk, especially for the immunocompromised, or those with eczema/atopic dermatitis. It is our long-term goal to establish a safe and effective vaccine regimen that includes the use of the currently approved, efficacious smallpox vaccine and an antiviral drug to prevent or treat adverse events particularly in the aforementioned high-risk populations. We hypothesize that co-administration of the smallpox vaccine and ST-246, an antiviral drug, to inhibit viral dissemination from the original site of inoculation, will significantly reduce vaccine-related pathologies in immunodeficient and eczematous hosts without compromising protective immunity elicited by the vaccine. Our hypothesis extends from previous observations: First, lethal poxvirus infections in humans and in animal models results from dissemination from the original site of inoculation and wide-spread systemic infection. Second, treatment of a normally lethal poxvirus infection, with ST-246, a drug that specifically blocks viral dissemination, is fully protective in numerous animal models. Third, we have completed pilot studies performed in immunocompetent mice, demonstrating that protective immunity elicited by the Dryvax(r) smallpox vaccine is in no way compromised by ST-246 and may in fact be enhanced. It remains to be seen whether ST-246 actually reduces the occurrence of vaccine-related adverse events. To evaluate whether ST-246 may improve the safety of the smallpox vaccine without compromising protective immunity, we propose to utilize murine models for immunodeficiency and eczema/atopic dermatitis as hosts for poxvirus challenge and ST-246 treatment. Toward this end, the following specific aims are proposed: [unreadable] 1. Evaluate the prophylactic and therapeutic efficacy of ST-246 in vaccinia-challenged murine models of B and T cell immunodeficiency. [unreadable] 2. Evaluate the prophylactic and therapeutic efficacy of ST-246 in vaccinia-challenged murine models of eczema/atopic dermatitis. [unreadable] 3. Analyze protective immune responses elicited by vaccination in combination with ST- 246 in immunodeficient and eczematous mice. [unreadable] [unreadable]